Glycans play important roles in antibody functions, and antibody glycoengineering has long been an important research field. Here, we summarize the significant strategies of antibody glycoengineering, including expressed antibody glycoengineering in mammalian cell expression systems, chemo-enzymatic antibody glycoengineering, and yeast expression system-based antibody engineering, as well as the applications of glycoengineering in antibody-drug conjugates. These advances in antibody glycoengineering will provide a comprehensive understanding and inspire us to develop more advanced techniques to achieve glycoengineered antibodies.
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http://dx.doi.org/10.1016/j.cbpa.2023.102420 | DOI Listing |
Org Biomol Chem
January 2025
School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou 310024, China.
Glycosite-specific antibody-drug conjugates (gsADCs), which carry cytotoxic payloads at the conserved -glycosylation site, N297, of an IgG, have emerged as a promising ADC format with better therapeutic index. Conjugating the payloads aldehyde-based chemistry is more friendly to IgGs, and has been widely investigated. However, the efficiency of introducing an aldehyde tag at the N297 site is poor due to the complicated procedures required, such as the multiple-enzyme-catalyzed IgG glycoengineering process and the successive oxidation step, which always results in heterogeneous products and poor stability.
View Article and Find Full Text PDFClin Lymphoma Myeloma Leuk
December 2024
Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY.
In the past decade, the treatment paradigm for chronic lymphocytic leukemia (CLL) has markedly shifted from traditional chemoimmunotherapy towards targeted therapies. A fixed-duration, targeted regimen with venetoclax, a potent oral BCL-2 inhibitor, combined with obinutuzumab, a glycoengineered type II anti-CD20 monoclonal antibody (Ven-Obi), has become the standard to beat for time-limited therapy in CLL. Ven-Obi allows for the rapid induction of remissions with high rates of undetectable minimal residual disease (uMRD) in patients across different treatment settings.
View Article and Find Full Text PDFBlood Adv
December 2024
Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.
Haemolytic disease of the foetus and newborn (HDFN) due to Rhesus D (RhD) antigen mismatch between the mother and foetus has been a significant cause of neonatal jaundice, recurrent miscarriage and stillbirth throughout history. Anti-RhD prophylaxis using polyclonal immunoglobulin G (RhD-pIgG) derived from the plasma of RhD-negative donors immunised with RhD-positive red blood cells (RBCs), has reduced the incidence of HDFN, but this approach is currently restricted to developed countries. Monoclonal antibodies (mAbs) offer a promising alternative to address this pressing need, but prior attempts to develop effective anti-RhD mAbs have failed, in some cases due to differences in fucosylation patterns between mAbs produced in cell lines and RhD-pIgG.
View Article and Find Full Text PDFbioRxiv
November 2024
Robert Frederick Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY 14853, USA.
Human immunoglobulin G (IgG) antibodies are one of the most important classes of biotherapeutic agents and undergo glycosylation at the conserved N297 site in the C2 domain, which is critical for IgG Fc effector functions and anti-inflammatory activity. Hence, technologies for producing authentically glycosylated IgGs are in high demand. While attempts to engineer for this purpose have been described, they have met limited success due in part to the lack of available oligosaccharyltransferase (OST) enzymes that can install linked glycans within the QYNST sequon of the IgG C2 domain.
View Article and Find Full Text PDFMAbs
November 2024
Lek d.d. Part of Sandoz, Biopharma Technical Development, Ljubljana, Slovenia.
Development of novel therapeutic proteins and biosimilars requires a thorough understanding of the relationship between their structure and function. Particularly, how IgG glycosylation affects its effector functions is a point increasingly underscored in guidelines by the World Health Organization and regulatory agencies. Our results show that just a 1% decrease in Fc fucosylation can lead to a more than 25% increase in antibody-dependent cell-mediated cytotoxicity.
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